The goal of this project is to use magnetic resonance imaging (MRI) to examine the natural history and potential therapeutic approaches in multiple sclerosis (MS). Emphasis has been placed on investigation of the early MS lesion which is characterized by enhancement on T1 weighted MRI images following administration of gadolinium-DTPA (GD). Results from initial studies have indicated that MS can be an active disease, even during periods of remission in the early, relapsing-remitting phase of the illness. The correlation between the frequency or area of Gd- enhancing lesions occurring in the cerebrum are clinically silent. Episodes of worsening tend to occur during periods of increased disease activity as evidenced by increased frequency or area of enhancing lesions. The clinical symptoms and signs generally are due to lesions occurring in the spinal cord or brain stem concurrently with the increased activity in the cerebrum. These results demonstrate a correlation between clinical worsening and periods of increased disease activity occurring in the cerebrum and indicate that the regulation of disease activity as measured by Gd enhancement seems similar in the cerebrum and spinal cord. Examination of the pathological changes occurring in conjunction with Gd enhancement indicate an acute inflammatory process with prominent perivascular cuffs of lymphocytes. These findings support the hypothesis that Gd enhancement represent the initial step in lesion development. The ability to use MRI as an outcome measure in clinical trials has been examined in a baseline, versus treatment trial design. The results of this study indicate response heterogeneity in patients treated with cyclosporine. Three patients out of ten had a dramatic reduction in MRI parameters, which based on analysis of the natural history data, is significant.